Effect of Iron Depletion by Phlebotomy Plus Lifestyle Changes vs. Lifestyle Changes Alone on Liver Damage in Patients With Nonalcoholic Fatty Liver Disease With Increased Iron Stores

Institute of Hospitalization and Scientific Care (IRCCS)

Status and phase

Unknown

Phase 3

Conditions

Nonalcoholic Fatty Liver Disease

Treatments

Other: Iron depletion treatment

Study type

Interventional

Funder types

Other

Identifiers

NCT00658164

111.2007

Details and patient eligibility

About

Patients will be randomized to lifestyle changes alone or lifestyle changes associated with iron depletion.

Iron depletion will be achieved by removing 350 cc of blood every 10-15 days according to baseline hemoglobin values and venesection tolerance, until ferritin < 30 ng/ml and transferrin saturation < 25%. Weekly phlebotomies will be allowed for carriers of the C282Y HFE mutation. Smaller phlebotomies (250 cc) will be allowed for carriers of beta-thalassaemia trait. Maintenance phlebotomies (as much as required) will then be instituted to keep iron stores depleted (ferritin < 50 ng/ml and transferrin saturation < 25%, MCV <85 fl). Before starting treatment, patients will undergo ECG, and in the presence of hyperglycemia or hypertension also echocardiography (see exclusion criteria).

Change in diabetes medication dosage or start of new therapy will be allowed for HbA1C values <6% or ≥ 7%. According to accepted criteria, previously untreated patients should be treated with metformin. If possible, newly diagnosed hypertension should be treated with Ace-inhibitors.

Enrollment

150 estimated patients

Sex

All

Ages

18 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age ≥ 18 < 75 years
Ferritin > 250 ng/ml and/or stainable iron at biopsy
NAS ≥ 2 and/or NAS 1 and stage≥1 at liver histology
Willingness to maintain diet and exercise during the full course of the study
Written informed consent to participate to the study and to have the specific genetic tests performed
Ability to comply with all study requirements

Exclusion criteria

Pregnant or lactating female
Diagnosis of or a history of:
Type 1 diabetes, diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g. Cushing's syndrome or acromegaly
Acute metabolic complication such as ketoacidosis or hyperosmolar state within the past 6 months
Alcohol consumption > 20 g/day for females and > 30 g/day for males
BMI ≥ 35 Kg/ m2
Other liver disease such as viral hepatitis, autoimmune hepatitis, Wilson disease, as defined by ceruloplasmin below normal limits and liver histology consistent with Wilson disease. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than 80 mg/dl or PiZ/PiZ or PiZ/PiS genotype. *Hemochromatosis, as defined by homozygosity for the C282Y HFE mutation or compound heterozygosity for C282Y/H63D mutations or Hepatic Iron Index ≥ 1.9.
Advanced liver disease (Child B/C cirrhosis), portal hypertension, hepatocellular carcinoma.
Congestive heart failure (NYHA I-IV) and unstable ischemic heart disease, systolic dysfunction (ejection fraction < 45%)
Any of the following ECG abnormalities: II or III degree Atrial Ventricular *Block, QT>500msec, repolarization defect suggestive of ischemia
Malignancy within the last 5 years
Serum creatinine levels > 1.5 mg/dl males, > 1.4 mg/dl females
TSH outside of normal range
Use of drugs known to induce NAFLD: corticosteroids, methotrexate, zidovudine, amiodarone, GH, estrogens, tamoxifene, tetracycline
Lipodystrophy, dysbetalipoproteinemia, inflammatory bowel disease, HIV infection
Basal hemoglobin levels < 11 g/dl